TuberculosisTuberculosis

Robert L. Copeland, Jr., Ph.D. Brian Tracy .

Hong FanDepartment of Respiratory Diseases,

West China Hospital, Sichuan University

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Introduction:Introduction:Infects 1/3 to ½ of world population..!3 million deaths due to TB every yearUnder privileged population -

Crowding, Poverty, malnutrition, single male..!

Since 1985 incidence is increasing in westAIDS, Diabetes, Immunosuppressedpatients, Diabetes, Drug resistance.

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Tuberculosis (TB) remains the leading cause of death worldwide from a single infectious disease agent. Indeed up to 1/2 of the world's population is infected with TB. The registered number of new cases of TB worldwide roughly correlates with economic conditions: the highest incidences are seen in those countries of Africa, Asia, and Latin America with the lowest gross national products. WHO estimates that eight million people get TB every year, of whom 95% live in developing countries. An estimated 2 million people die from TB every year.

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It is estimated that between 2000 and 2020, nearly one billion people will be newly infected, 200 million people will get sick, and 35 million will diefrom TB - if control is not further strengthened. The mechanisms, pathogenesis, and prophylaxis knowledge is minimal. After a century of decline TB is increasing and there are strains emerging which are resistant to antibiotics. This excess of cases is attributable to the changes in the social structure in cities, the human immunodeficiency virus epidemic, and failure of most cities to improve public health programs, and the economic cost of treating.

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With the increased incidence of AIDS, TB has become more a problem in the U.S., and the world.It is currently estimated that 1/2 of the world's population (3.1 billion) is infected with Mycobacterium tuberculosis. Mycobacterium avium complex is associated with AIDS related TB.

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TB is an ancient infectious disease caused by Mycobacterium tuberculosis. It has been known since 1000 B.C., so it not a new disease. Since TB is a disease of respiratory transmission, optimal conditions for transmission include:

overcrowding poor personal hygiene poor public hygiene

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TransmissionTransmissionPulmonary tuberculosis is a disease of respiratory transmission, Patients with the active disease (bacilli) expel them into the air by:

coughing, sneezing, shouting,or any other way that will expel bacilli into the air

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Once inhaled by a tuberculin free person, the bacilli multiply 4 -6 weeks and spreads throughout the body. The bacilli implant in areas of high partial pressure of oxygen: lung renal cortex reticuloendothelial system

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This is known as the primary infection. The patient will heal and a scar will appear in the infected loci. There will also be a few viable bacilli/spores may remain in these areas (particularly in the lung). The bacteria at this time goes into a dormant state, as long as the person's immune system remains active and functions normally this person isn't bothered by the dormant bacillus.When a person's immune system is depressed., a secondary reactivation occurs. 85-90% of the cases seen which are of secondary reactivation type occurs in the lungs.

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Pathogenesis of TB:Pathogenesis of TB:

Type IV hypersensitivity – T cells –Macrophages GranulomaActivated macrophages – epithelioid cells.Remain viable inside macrophages (Mycolicacid wax coat)Cord Factor - surface glycolipid Antigenic.Self destruction by lysosomal enzymes.

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Hypersensitity Hypersensitity –– ImmunityImmunity

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Microbiology of TB:Microbiology of TB:Mycobacteria – ‘fungus like.. Bacilli, Aerobic, non motile, no toxins, no spore. Mycolic acid wax in cell wall Carbol dye - Acid & alcohol fast (AFB)M. tuberculosis & M. bovisM. avium, M.intracellulare in AIDS -Atypical TB

AFB AFB -- ZiehlZiehl--Nielson stainNielson stain

Colony Morphology Colony Morphology –– LJ SlantLJ Slant

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Classification of TB

1. Primary Pulmonary TB2. Miliary TB (acute, subacute, chronic)3. Secondary TB

(invasive, carvitary, caseation ,Tuberculous GranulomasTuberculous Granulomas …)

4. TuberculousTuberculous Pleuritis5. Extra-pulmonary TB

(bone, joints, renal, adrenal,skin… )

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Primary tuberculosisPrimary tuberculosisIn a non immunized individual – children* adult*Deep inhalation of airborne droplet ~ 3 microns.Bacilli locate in the subpleural mid zone of lung Localized "atypical" pneumonia Brief acute inflammation – neutrophils.5-6 days invoke granuloma formation. 2 to 8 weeks – healing – single round -Ghon focus.If lymph node is also involved Ghon complex.

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Primary or Primary or GhonGhon’’ss ComplexComplex

Primary tuberculosis is the pattern seen with initial infection with tuberculosis in children.Reactivation, or secondary tuberculosis, is more typically seen in adults.

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Primary TuberculosisPrimary TuberculosisIn Non Immunized individuals (Children)Primary Tuberculosis:

Self Limited diseaseGhons focus, complex or Primary complex.

Primary Progressive TB ( in US. )Miliary TB and TB Meningitis.Common in malnourished children 10% of adults, Immuno-suppressed individuals

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Secondary Tuberculosis:Secondary Tuberculosis:

Post Primary in immunized individuals. Cavitary Granulomatous response.Reactivation or ReinfectionApical lobes or upper part of lower lobes – O2Caseation, cavity - soft granulomaPulmonary or extra-pulmonary Local or systemic spread / Miliary

Vein – via left ventricle to whole bodyArtery – miliary spread within the lung

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Secondary Tuberculosis:Secondary Tuberculosis:

Reactivation occurs in 10-15% of patients.Most commonly males 30-50 ySlowly Progressive (several months)Cough, sputum, Low grade fever, night sweats, fatigue and weight loss.Hemoptysis or pleuritic pain = severe disease

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GhonGhon ComplexComplex

MiliaryMiliary TBTB

MiliaryMiliary TBTBMillet like – grain.Extensive micro spread.Through blood or bronchial spreadLow immunityPulmonary or Systemic types.

MiliaryMiliary TB Lung TB Lung

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CavitaryCavitary TuberculosisTuberculosisWhen necrotic tissue is coughed up cavity. Cavitation is typical for large granulomas. Cavitation is more common in the secondary reactivation tuberculosis - upper lobes.

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TuberculousTuberculous GranulomasGranulomas

CaseationCaseation NecrosisNecrosis

EpitheloidEpitheloid cells in cells in GranulomaGranuloma

Cells in Cells in GranulomaGranuloma

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Morphology of Morphology of GranulomaGranuloma1. Rounded tight collection of chronic

inflammatory cells.2. Central Caseous necrosis.3. Active macrophages - epithelioid cells.4. Outer layer of lymphocytes, plasma cells

& fibroblasts.5. Langhans giant cells – joined epithelioid

cells.

TuberculousTuberculous GranulomaGranuloma

CavitaryCavitary Secondary TBSecondary TB

Systemic Systemic MiliaryMiliary TBTB

Adrenal TB Adrenal TB -- Addison DiseaseAddison Disease

Spinal TB Spinal TB -- Potts DiseasePotts Disease

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Diagnosis of TBDiagnosis of TBClinical features are not confirmatory.Zeil Nielson Stain - 1x104/ml, 60% sensitivityRelease of acid-fast bacilli from cavities intermittent.3 negative smears to assure low infectivity*Culture most sensitive and specific test.

Conventional Lowenstein Jensen media 3-6 wks.Automated techniques within 9-16 days

PCR is available, but should only be performed by experienced laboratoriesPPD for clinical activity / exposure sometime in life.

PPD Tuberculin TestingPPD Tuberculin TestingSub cutaneousWeal formationItching – no scratch.Read after 72 hours.Induration size. 5-10-15mm (non-ende)< 72 hour is not diag*+ve after 2-4 weeks.BCG gives + result.

PPD TestingPPD Testing

GranulomaGranuloma or LH giant cell is or LH giant cell is notnotpathagnomonicpathagnomonic of TBof TB……!!

Foreign body granuloma.Fat necrosis.Fungal infections.Sarcoidosis.Crohns disease.

""Troubles are often Troubles are often the tools by which God the tools by which God fashions us for better fashions us for better

things." things."

- Henry Ward Beecher

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Classification of DrugsClassification of Drugs3 Groups depending upon the degree of effectiveness and potential side effects

First Line: (Primary agents)are the most effective and have lowest toxicity. Isoniazid(H), Rifampin(R)

Second Line:Less effective and more toxic effectsinclude (in no particular order): p-amino salicylic acid, Streptomycin(S), pyrazinamide(Z), Ethambutol(E),

Third Lineare least effective and most toxic. Amikacin, Kanamycin, Capreomycin, Viomycin, Kanamycin, Cycloserine

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IsoniazidIsoniazid

Considered the drug of choice for the chemotherapy of TB. discovered in 1945 a hydrazide of isonicotonic acid

is bacteriostatic for resting bacilli, bactericidal for growing bacilli.

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TreatmentTreatment2HRZE/4HRE, 2HRSE/4HRE

( 6---18months ) in China(in the U.S. ,Isoniazid, Ethambutol, & Rifampin are

given for 2 months. Isoniazid & Rifampin are given for 4 months. If you suspect resistance to isoniazid use (HRZE)Isoniazid, Ethambutol, Rifampin & Parazinamide. Incidence of drug resistance is 2-5% in the U.S. )Prolonged bed rest is not necessary or helpful in obtaining a speedy recovery. The patient must be seen at regular and frequent intervals to follow the course of the disease and treatment. Look for toxic effects

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Chemoprophylaxis of TBChemoprophylaxis of TBUsed only in high risk groupsUsed only in high risk groups

Household members and other close contacts of a patient with active TB.A positive skin test in persons less than 35 years.A positive skin test reactive in the immunosuppressed, persons with leukemia, and Hodgkin's Disease,HIV + patients with a positive TB test,( INH 300mg/d, 6—8m. )

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The drug of choice for chemoprophylaxis is isoniazid. Prophylaxis uses only one drug. In patients who are HIV+ and TB+ and have the disease; they are treated for a minimum of 9 months, 2HR/7HR?? ?

(The first 2 months using HR(isoniazid and rifampin) and for the next 7 months or longer, use only 2 or 3 of the 2nd/3rd line drugs and Isoniazid/Rifampin. )

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Conclusions:Conclusions:A chronic, common, infectious disease - Weight loss, fever, night sweats, lung damage.Commonest fatal infectious disease in the world.CXR – apical of upper lob, basal of lower lob lesions (CXR atypical AIDS)AIDS, Diabetes, malnutrition (poverty), crowding. Five / (Two forms Primary, Secondary in US.)Pulmonary,miliary,invasive,pleuritis,extrapulmonary,.AFB(sputum stain +) - infectiousness - isolationto prevent selection of resistance

Prevention depends on PPD & INH prophylaxis

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WARNING!WARNING!

Rifampin and Isoniazid are the most effective drugs for the treatment of TB, The drug enjoys high patient compliance and acceptability. But these 2 drugs shouldnever be given alone! They are always used in combination because resistance occurs to one drug alone very rapidly. They are used in combination with each other initially as well as other drugs. Bacilli must become resistant to two drugs in order to remain viable. Statistically, the chances are verv small of the bacilli becoming resistant to both. . Prophylaxis is with one drug usually isoniazid.

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What is NewWhat is New……??14-30% of TB patients also HIV infected.New drugs - Rifapentine, Interferons, Thalidomide.Immune therapy : Killed M. vaccine stimulates CD8 cells (increased INF and IL-12). The genome of TB has been identified (~4000 genes) potential to develop new vaccines and tests.

""When you are faced by When you are faced by the consequences of past the consequences of past choices, You see the gift choices, You see the gift of a lesson rather than a of a lesson rather than a curse of a fall.curse of a fall.

Brian Tracy